DESCRIPTION Nicotine acts as an agonist on a class of ligand-gated ion channels in the brain, the neuronal nicotinic acetylcholine receptors (nAChR) that differ one from another in their pharmacological and functional properties. The alpha7 nAChR is a member of this family that is a homo-oligomeric receptor, highly permeable to calcium. In addition to its role in modulating release of neurotransmitter from the nerve terminal, there is evidence that the alpha7 receptor has a role in neuronal differentiation and is developmentally regulated in the central nervous system. Recent studies have shown that a threonine for leucine substitution at position 247 (L247T) in the channel domain of the alpha7 nAChR increases agonist affinity, decreases the rate of desensitization and gives rise to an additional channel conductance. This altered form of the alpha7 receptor presents an ideal candidate for creating a "gain of function" animal model. Thus, to further understand the role of the alpha7 nAChR in the central nervous system, our laboratory has helped generate mice that stably express the L247T mutant form of this receptor. The overall goal of this present proposal is mice that stably express the L247T mutant form of this receptor. The overall goal of the present proposal is to carry out a detailed examination of the anatomical, molecular and behavioral characteristics of alpha7 L247T to carry out a detailed examination of the anatomical, molecular and behavioral characteristics of alpha7 L247T mutant mice. The first aim will be to use histological, pharmacological, biochemical, molecular and behavioral approaches to characterize and compare L247T mutant mice to their wild-type littermates. The second aim will test the hypothesis that alpha7 L247T nAChRs are potentially responsible for the increased apoptosis observed in the brains of L247T homozygous mice by comparing the ontogeny of TUNEL.